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Abstract

Introduction

Altered pharmacokinetics (PK) in critically ill patients can result in insufficient
serum β-lactam concentrations when standard dosages are administered. Previous studies
on β-lactam PK have generally excluded the most severely ill patients, or were conducted
during the steady-state period of treatment. The aim of our study was to determine
whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem
would result in adequate serum drug concentrations in patients with severe sepsis
and septic shock.

Methods

Open, prospective, multicenter study in four Belgian intensive care units. All consecutive
patients with a diagnosis of severe sepsis or septic shock, in whom treatment with
the study drugs was indicated, were included. Serum concentrations of the antibiotics
were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5
and 6 or 8 hours after administration.

Conclusions

Serum concentrations of the antibiotic after the first dose were acceptable only for
meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime
may, therefore, be insufficient to empirically cover less susceptible pathogens in
the early phase of severe sepsis and septic shock.

Introduction

Severe sepsis and septic shock remain a major cause of morbidity and mortality in
medical and surgical ICUs [1]. Although early and appropriate antibacterial therapy is considered a priority in
the management of patients with sepsis [2,3], there is evidence that optimizing antibiotic dosage regimens to achieve therapeutic
concentrations in the blood and at the site of infection is equally important [4].

Antibiotherapy in critically ill septic patients usually consists of a broad-spectrum
β-lactam combined with a glycopeptide and/or an aminoglycoside [5]. These drugs cover a large variety of pathogens and can be empirically used for Gram-negative
bacterial infections, including those caused by Pseudomonas aeruginosa. The activity of β-lactams is predominantly time-dependent and requires serum and
tissue antibiotic concentrations above the minimal inhibitory concentration (MIC)
of the pathogen to achieve adequate bacterial killing [6]. This effect is independent of peak levels and there is no significant post-antibiotic
effect, except for carbapenems. Clinical data suggest that maximum killing of bacteria
occurs when serum concentrations are maintained above the MIC of the causative pathogens
for extended periods [7,8]; this may be especially appropriate in patients with compromised host-defences, including
critically ill patients [9,10]. However, in conventional bolus dosing regimens, serum β-lactam concentrations may
fall to low levels between doses [11,12], with potentially negative effects on clinical response and emergence of resistances.

Antibiotic dosage regimens used in ICU patients are often based on pharmacokinetic
(PK) data that were obtained in healthy volunteers or less severely ill patients.
Moreover, they rarely take into account the dynamic changes of the septic process
that can reduce the efficacy of anti-infective treatments and consequently affect
patient outcomes [6]. During severe sepsis and septic shock, increased volume of distribution (Vd) and
cardiac output can reduce serum drug concentrations, whereas decreased protein binding
and end-organ dysfunction induce higher antibiotic levels [13]. Optimizing antibiotic dosage strategy should involve PK parameters, but therapeutic
drug monitoring is necessary in septic patients because large inter-individual PK
variations make it difficult to predict antibiotic levels [14]. As previous PK studies on β-lactams in ICU patients have excluded the most severely
ill patients or were conducted in the steady-state period of treatment [15-17], the main objective of this study was to determine whether the currently recommended
first dose of four broad-spectrum β-lactams (piperacillin-tazobactam, ceftazidime,
cefepime, and meropenem) provide adequate plasma concentrations in critically ill
septic patients in the ICU. We also tried to determine whether clinical or hemodynamic
parameters could affect the PK profile of these drugs during such severe infections.

Materials and methods

Study design, patients, antibiotic treatment and data collection

This was a prospective, multicenter, observational study performed in four Departments
of Intensive Care in Belgium (at the St-Luc Hospital, Erasme Hospital, and UZ-VUB
in Brussels and St Pierre Hospital in Ottignies). The study protocol was approved
by the university ethics committees of the different hospitals. Before enrolment,
written consent was obtained from the patient or their nearest relative.

All patients admitted to one of the four ICUs between January 2005 and July 2006 were
considered for inclusion. Inclusion criteria were a diagnosis of severe sepsis or
septic shock [18], either at admission or during the ICU stay, and treatment with a broad-spectrum
β-lactam antibiotic (ceftazidime, cefepime, piperacillin-tazobactam, or meropenem).
Patients meeting one of the following criteria were excluded: age less than 18 years
or more than 85 years; pregnancy or lactation; previous administration of any of the
investigated antibiotics; chronic renal failure requiring dialysis; or allergy to
any of the investigated antibiotics. The study period was limited to the first 24
hours of antibiotherapy.

Administration of the four β-lactams was made according to local guidelines. These
drugs are generally used in the participating centers to treat hospital- or ICU-acquired
infections or in the case of community-acquired infection when a more-resistant pathogen
may be involved (recent hospitalization or antibiotic therapy, previous colonization
by more resistant strain). Piperacillin-tazobactam was preferred as first-line therapy
in cases of proven or suspected intra-abdominal infections. Ceftazidime and cefepime
was used as first-line therapy in other cases. Meropenem was used as second-line therapy
(i.e. failure of piperacillin-tazobactam or cephalosporins) or in case of suspected
or previous colonization by extended spectrum beta-lactamase Gram-negative bacteria.

In all study patients, demographics, pre-existing chronic diseases, admission diagnosis
and biological data were collected in institutional databases. The severity of illness
of each patient was characterized using the Acute Physiology and Chronic Health Evaluation
(APACHE) II [19] and sequential organ failure assessment (SOFA) [20] scores determined on the first day of antibiotic treatment. Creatinine clearance
(CrCl) was calculated using a standard formula [21]. Treatment of patients with catecholamines, mechanical ventilation, hemofiltration
or hemodialysis was recorded, as was length of ICU and hospital stay, overall mortality,
and cause of death. Hemodynamic data were collected at baseline, and 8 and 24 hours
after the start of the protocol.

Analytic method for β-lactams

All the patients included in the study received a first dose of 2 g ceftazidime or
cefepime, 4 g/0.5 g piperacillin-tazobactam, or 1 g meropenem. The usual daily doses
of these antibiotics and dose adjustments for renal function are presented in Additional
file 1. All the patients also received amikacin and the two antibiotics were administered
simultaneously over 30 minutes using an infusion pump. Blood samples of 5 mL were
collected without anticoagulant immediately before the infusion (0 hour) and 1, 1.5,
4.5, and 6 or 8 hours (depending on the frequency of administration of the β-lactam)
thereafter; these blood-draw time points were chosen as they belong to the elimination
phase of all four antibiotics. The exact sampling time was recorded by the nursing
or medical staff. Blood samples were centrifuged at 4000 g for 10 minutes after blood
clotting. To allow for possible drug instability at room temperature, serum samples
were stored at -80°C until analysis.

All antibiotic quantitative analyses were performed in a centralized reference laboratory
(St Luc Hospital). Importantly, as the PK of piperacillin and tazobactam are highly
correlated [22], we only measured piperacillin levels. Serum β-lactam concentrations were determined
by high-performance liquid chromatography with diode array detection. The intravenous
antibiotic formulations were reconstituted according to the manufacturers' recommendations
and diluted in water in order to reach stock solution aliquots of 1 mg/mL, stored
at -20°C. Before each assay, a fresh calibration curve was prepared from the stock
solution and blank serum at the following concentrations: 0.75, 1, 2, 5, 10, 25, and
50 μg/mL for piperacillin-tazobactam; 5, 10, 25, 50, and 100 μg/mL for ceftazidime;
0.1, 0.25, 0.5, 1, 5, 10, 25, and 50 μg/mL for cefepime or meropenem. The calibration
and liquid-liquid extraction procedures as well as chromatographic conditions have
been described previously [23]. The validation of the four analytical methods was performed over a three-day period
with five calibration curves per day (i.e., 15 serum samples per concentration level).
All methods were validated according to the published acceptance criteria for specificity,
linearity, accuracy, precision (intra-day (repeatability), inter-day (intermediate
precision)) and sensitivity (limit of detection (LOD) and limit of quantification
(LOQ)). Specificity was determined by the ability to identify the β-lactam from its
characteristic retention time and ultraviolet spectrum, and the fine resolution of
its chromatographic peak. The linearity of the calibration curve was demonstrated
by a significant linear regression analysis, with a determination coefficient (r2) more than 0.99. Accuracy was expressed as the percent deviation of the mean observed
concentration from the theoretical value, which should not exceed 15%, except at the
LOQ (20%). Precision was acceptable if the intra- and inter-day coefficients of variation
(CV) were 20% or less at the LOQ and 15% or less at all other concentrations. LOQ
was defined as the lowest concentration of the calibration curve, which could be reliably
differentiated from background noise with a signal-to-noise ratio of at least 10:1
and quantified with acceptable accuracy (80 to 120%) and precision (CV ≤ 20%); LOD
was defined as the lowest concentration that could be detected and reliably differentiated
from background noise with a signal-to-noise ratio of at least 3:1.

The carry-over effect was tested by injecting regular blank samples and ultrapure
water into the high-performance liquid chromatography system after high concentration
calibrators. Under the described chromatographic conditions, piperacillin-tazobactam,
ceftazidime, cefepime, and meropenem were identified by sharp and well-resolved peaks.
The linearity was statistically confirmed over the concentration range tested for
each β-lactam and was associated with an r2 of more than 0.999. The four analytical methods were accurate and precise. LOD and
LOQ were 0.50 and 0.75 μg/mL, respectively, for piperacillin-tazobactam, 2.00 and
5.00 μg/mL for ceftazidime, and 0.07 and 0.10 μg/mL for cefepime and meropenem. Appropriate
dilution was performed for clinical samples with concentrations above the upper analytic
range (corresponding to the calibration curve).

PK analysis

The PK of the four antibiotics was individually assessed using WinNonlin Professional
version 5.0.1. software (Pharsight Corporation, Mountain View, CA, USA). A one-compartment
model with first-order elimination was selected to fit the data. Investigated PK parameters
included maximal serum concentration (Cmax, calculated by extrapolation of the elimination
phase at the end of the infusion) Vd, total clearance (CL), elimination half-live
(t1/2) and area under the serum concentration-time curve (AUC). Vd and CL were normalized
to the body weight.

PK end-points

The threshold of MIC required for maximal β-lactam activity is still controversial.
In this study, the adequacy of β-lactam therapy was assessed by calculating the time
spent greater than four times the target MIC (T > 4 × MIC). For each drug, the optimal
T > 4 × MIC was considered as: above 50% for piperacillin-tazobactam, above 70% for
ceftazidime and cefepime, and above 40% for meropenem in Gram-negative bacterial infections
[24]. As the dosage interval of β-lactams is prolonged in renal impairment [see Additional
file 1], we calculated the time before the subsequent administration according to the adjustment
of the drug regimen to CrCl for each patient. As there is a large variance in MIC
values for different bacteria, we considered the MICs for problematic pathogens, such
as P. aeruginosa, commonly isolated in ICU patients, as the empiric target threshold [25]. Sensitivity thresholds of MIC for this pathogen, as defined by European Committee
on Antimicrobial Susceptibility Testing (EUCAST), are: 8 μg/mL or less (ceftazidime,
cefepime), 16 μg/mL or less (piperacillin-tazobactam), and 2 μg/mL or less (meropenem)
[see Additional file 1] [26]. We, therefore, classified each patient as having an 'adequate' or 'inadequate' PK
profile according to the percentage of time during which serum drug concentrations
remained more than four times the clinical breakpoint for P. aeruginosa (% T > 4 × MIC): 32 μg/mL or more (ceftazidime, cefepime), 64 μg/mL or more (piperacillin-tazobactam),
and 8 μg/mL or more (meropenem). Finally, by simulation using the PK parameters of
our population, we calculated the probability of achieving target T > 4 × MIC values
for other MICs that can be found in ICU-isolated Gram-negative bacteria.

Statistical analysis

Statistical analyses were performed using the SPSS 13.0 for Windows NT software package
(SPSS Inc. 2004, Chicago, IL, USA). Descriptive statistics were computed for all study
variables. A Kolmogorov-Smirnov test was used, and histograms and normal-quantile
plots were examined to verify the normality of distribution of continuous variables.
Discrete variables were expressed as counts (percentage) and continuous variables
as means ± standard deviation or median (25th to 75th percentiles). Demographics and
clinical differences between study groups were assessed using a chi-squared, Fisher's
exact test, Student's t-test, or Mann-Whitney U test, as appropriate. The Pearson's
(r) correlation coefficient was used to determine linear correlation as appropriate.
Association between variables was tested by simple regression analysis and coefficient
of determination (R2) in case of non-linear correlation. A P < 0.05 was considered as statistically significant.

Results

Patient characteristics

We enrolled 80 patients (mean age 63 years, 64% male; Table 1) in the current study. Fifty-five (69%) of the patients were medical admissions and
55 had a hospital or ICU-acquired infection; 58 (72%) had septic shock. The median
APACHE II score was 22 and the median SOFA score on admission was 8. Fifty-seven patients
(71%) were treated with mechanical ventilation; 22 patients (27%) had acute renal
failure. Overall ICU mortality was 38%, mostly due to sepsis. Most infections were
respiratory or abdominal and were microbiologically documented in 56 patients (70%).
Blood cultures were positive in 32 patients (40%). Forty (50%) cases of sepsis were
secondary to Gram-negative bacilli, with 36 infections due to difficult-to-treat pathogens
(P. aeruginosa (n = 18); Enterobacter species (n = 11); Citrobacter freundii, Hafnia alvei and Morganella morganii (n = 2 for each); Serratia marcescens (n = 1)).

Table 1. Characteristics, hemodynamic and biological data on admission and fluid balance during
the first 24 hours (n = 80)

Pharmacokinetic data

Of the 80 patients, 16 were treated with meropenem, 18 with ceftazidime, 19 with cefepime,
and 27 with piperacillin-tazobactam. The mean PK parameters for the four drugs are
shown in Table 2. There was marked inter-individual variation in all PK parameters; Vd was increased
for all four drugs when compared with healthy volunteers, with consequently a lower
Cmax [see Additional file 1]. The median total CL was also reduced when compared with the median CL in healthy
volunteers. The median percentage of T > 4 × MIC was 57% for meropenem, 45% for ceftazidime,
34% for cefepime, and 33% for piperacillin-tazobactam (Table 3). Thirteen patients had plasma concentrations less than four times the target MIC
after only 90 minutes (ceftazidime = 1; cefepime = 1; piperacillin-tazobactam = 11).
The number of patients who attained the target percentage T > 4 × MIC was 12 of 16
for meropenem (75%), 5 of 18 for ceftazidime (28%), 3 of 19 (16%) for cefepime, and
12 of 27 (44%) for piperacillin-tazobactam.

Table 3. Adequate concentrations of the four drugs, with regard to renal dysfunction

Drug regimens were adapted because of renal impairment in 41 patients (6 treated with
meropenem, 9 with ceftazidime, 12 with cefepime, and 14 with piperacillin-tazobactam).
The CrCl was similar among the four groups (piperacillin-tazobactam 56 (ranges: 13
to 164) mL/min; meropenem 64 (22 to 134) mL/min; ceftazidime 58 (15 to 145) mL/min;
cefepime 40 (13 to 150) mL/min). In patients with renal dysfunction (CrCl <50 mL/min),
5 of 6 (83%) attained the target concentration for meropenem, 3 of 9 (33%) for ceftazidime,
2 of 12 (17%) for cefepime, and 10 of 14 (71%) for piperacillin-tazobactam. For piperacillin-tazobactam,
but not for the other antibiotics, patients with renal dysfunction had a significantly
higher probability of having adequate drug concentrations than patients with normal
renal function (10 of 14 vs. 2 of 13, P = 0.03). Calculating the probability of target T > 4 × MIC attainment for several
MICs, values more than 90% were obtained for ceftazidime and piperacillin-tazobactam
with MIC of 2 μg/mL or less and for cefepime and meropenem with MIC of 1 μg/mL or
less (Table 4).

Correlation with clinical variables

No correlation was found between the T > 4 × MIC and any hemodynamic or clinical variable
for any of the four drugs, including age, mechanical ventilation, APACHE II or SOFA
score at admission, presence of shock, maximum dose of vasopressor agents or fluid
balance. There was a significant correlation between CrCl at admission and CL for
all drugs (data not shown).

Discussion

In this study, we show that current standard first doses of piperacillin-tazobactam,
cefepime and ceftazidime are insufficient to maintain therapeutic serum concentrations
greater than four times the MIC of P. aeruginosa in patients with severe sepsis and septic shock. Only with meropenem did a large percentage
of patients achieve the bactericidal target of at least 40% T > 4 × MIC. Nevertheless,
the probability of reaching the target concentration was greater than 90% only for
MICs of 1 μg/mL or less for cefepime, and MICs of 2 μg/mL or less for ceftazidime
and piperacillin-tazobactam, suggesting that, for all these drugs, insufficient drug
concentrations are obtained for pathogens with higher MICs.

Broad spectrum β-lactams are active against most organisms recovered from ICU patients.
Because of the emergence of multidrug-resistant strains and the lack of new antibiotics
effective against Gram-negative bacteria [27], a more effective use of existing therapies is necessary. In vivo animal studies have demonstrated that β-lactams have a slow continuous kill characteristic
that is almost entirely related to the time during which concentrations in tissue
and serum exceed the MIC (T > MIC) for the infecting organism [28,29]. The time above the MIC required for maximal β-lactam activity may differ depending
on the drug as well as on the pathogen [24]. It has been proposed that, in the absence of post-antibiotic effects, the serum
concentration of a β-lactam should exceed the MIC for the respective organism for
100% of the dosing interval [30]. However, experimental studies have suggested that maximum killing of bacteria occurs
when β-lactam concentrations exceed four to five times the MIC of the infecting pathogen
for extended periods [31,32]. For the treatment of infections in humans, optimal β-lactam concentrations are still
controversial. Clinical confirmation of the PK parameters needed for optimal β-lactam
efficacy is limited because in several studies drug levels were not measured and the
patients included had infections caused mostly by sensitive bacteria [33]. In patients treated with cephalosporins, T > MIC of 100% was associated with greater
clinical cure and bacteriological eradication than T > MIC less than 100% [9]. However, the bactericidal activity of cephalosporins has also been shown to be optimal
at drug concentrations of about four times the MIC [7]. Even if we preferred 4 × MIC as PK end-point in this study, we did not have enough
data to compare the efficacy of these two strategies in the human setting, and a prospective
study evaluating the different β-lactams concentrations in the treatment of severe
infections is necessary.

Studies on serum concentrations of broad-spectrum β-lactams have already reported
that drug levels are insufficient in patients with severe infections. Cefepime (2
g every 12 hours) concentrations were more than 70% T > 16 μg/mL in less than half
the patients with sepsis [15] and were adequate only for MICs of 4 μg/mL in all eight patients suffering from post-operative
infections [34]. Septic patients with normal renal function had serum cefepime and ceftazidime levels
less than 32 μg/mL after a few hours in most cases [11,12]. Ceftazidime trough concentrations were below the median MIC of P. aeruginosa in more than half of the patients in another study [35]. In only one study, ceftazidime levels were above the MIC of the isolated pathogens
for more than 90% of the time interval; however Pseudomonas was isolated in only 4 of 16 patients [16]. Finally, piperacillin concentrations were above therapeutic levels (64 μg/mL) for
most of the time interval in patients with sepsis [36] or nosocomial pneumonia [37]. However, serum drug concentrations of meropenem were adequate in most of the patients.
In severe infections associated with septicemia, mostly after cardiac surgery, meropenem
had serum concentrations above 8 μg/mL for at least 50% of the time in patients with
normal and those with reduced CrCl [38]. In patients with ventilator-associated pneumonia, mean T > 4 × MIC for Pseudomonas was reported as 52% in one study [39] and 46% in another [17].

Nevertheless, most of these previous studies excluded severely ill patients with septic
shock and those with an estimated CrCl limiting the generalization of their results
to other populations of critically ill patients. The number of patients was also limited
and analyses concerned only the steady-state of the disease. Finally, some of these
studies used lower than recommended dosage regimens, which are associated with an
increased mortality when susceptible pathogens with higher MICs are present [40,41]. Our study focused on a more severe population of patients, suffering from severe
sepsis and septic shock, with higher mortality and morbidity rates than less severely
ill ICU populations [42]. Importantly, we used recommended β-lactam regimens that have the greatest likelihood
of achieving a bactericidal target in nosocomial pneumonia and bloodstream infections
due to Gram-negative bacteria [43,44]. Finally, because antimicrobial treatment of sepsis is often initiated empirically,
when pathogens and MICs are still unknown, we used as the target MIC the clinical
breakpoint defined by EUCAST for P. aeruginosa, an organism that is commonly isolated in ICUs and associated with high mortality
rates [25]. This strategy could then be extrapolated to other 'difficult-to-treat' pathogens
with high susceptibility breakpoints.

The consequences of these low antimicrobial levels may be more cases of therapeutic
failure, higher medical costs and greater emergence of resistance [45]. Moreover, low plasma levels can contribute to lower than expected β-lactam concentrations
in the extracellular [46], bronchial [47] or peritoneal fluid [48] with potentially reduced antimicrobial delivery to the target tissues. In view of
these results, in septic patients, broad-spectrum β-lactams should be administered
more frequently than suggested in non-septic patients, or with doses larger than standard
regimens to optimize pathogen exposure to bactericidal concentrations of the drugs.
Population modeling simulation showed that continuous or extended β-lactam infusions
are required to obtain adequate serum concentrations [45]. However, clinical data that have shown a better outcome using this strategy have
come just from retrospective studies in ICU populations with pneumonia [49,50]. Further studies are needed in ICU patients to assess the influence on morbidity
and mortality of a strategy whereby antibiotic therapy is selected based on the optimal
PK, especially in patients with sepsis and in infections caused by multiresistant
pathogens.

Although a relation between the intensity of the septic process and PK abnormalities
can be assumed, we did not find any relation between T > 4 × MIC and any demographic,
clinical, hemodynamic or biological variables. This finding may be related to the
fact that the PK analyses were performed during the early phase of sepsis. Also, as
a first dose of antibiotic is largely influenced by Vd, the increased distribution
volume may play a key role in reducing antimicrobial concentrations in this setting
whereas drug clearance remains the main determinant for drug concentrations at steady-state
[13]. CrCl and drug CL showed good correlation, as elimination of the studied drugs is
largely dependent on glomerular function [11,38]. Nevertheless, despite a regimen adapted to renal function, patients treated with
piperacillin-tazobactam had a higher percentage of adequate concentrations when CrCl
was below 50 mL/min. This finding may be related to the complex elimination of piperacillin-tazobactam,
which includes biliary excretion [13]. Indeed, the hepatic metabolism of this drug is variable and difficult to measure
and most studies on piperacillin-tazobactam PKs in patients with renal failure have
included patients with normal hepatic function [51]. It is possible that, as severe sepsis is frequently associated with liver dysfunction,
this may have contributed to greater than expected drug accumulation in some patients.
Further studies are needed to evaluate the impact of renal and hepatic dysfunction
on piperacillin-tazobactam regimens in critically ill patients.

Our study has some limitations. First, we evaluated the PK profile of β-lactams only
during the first dose, and thus cannot make any statement with regard to subsequent
doses. Vd may decrease during therapy when capillary leakage subsides and sepsis resolves
[52]; in such circumstances, coupled with persistent renal dysfunction, standard β-lactam
doses may be sufficient to achieve therapeutic concentrations. Second, as only free
drug is the active moiety, it has been recommended that all PK/pharmacodynamic indices
should be referenced to the unbound (free) fraction of the drug, especially for some
drugs such as piperacillin, which has 20 to 30% protein binding [53]. Third, the inadequate PK/pharmacodynamic indices observed in our study should be
considered in relation to the empirical MIC target, and may be different with other
susceptibility patterns (MIC distributions) of pathogens at individual institutions.
Attention should therefore be paid to establish the MIC values of these pathogens
in order to adapt dosage regimens. Also, CrCl was estimated using the Cockroft and
Gault formula, which shows important limitations in predicting the real CrCl in ICU
patients [54]. Finally, the four groups were heterogeneous and, therefore, the numbers may be too
small to fully reflect the characteristics of the drugs in this setting. However,
an important concern is the highly variable and unpredictable inter-individual PKs
for cephalosporins and piperacillin and whether these drugs can be considered an appropriate
agent to use as initial empirical therapy for critically ill patients with severe
sepsis and septic shock, particularly in those with potentially less susceptible Gram-negative
bacterial strains.

Conclusions

The treatment of infections in the critically ill patient remains a significant challenge
for clinicians. Standard first doses of broad-spectrum β-lactams provided inadequate
levels to achieve target serum concentrations for extended periods of time in critically
ill patients with sepsis. Improved characterization of the pharmacodynamic properties
of these antimicrobials may lead to revisions in recommendations on dosing in severe
infections, especially in the early phase of severe sepsis and septic shock.

Key messages

• Recommended doses of piperacillin-tazobactam, cefepime and ceftazidime provided
serum drug concentrations during the first 24 hours of treatment that were insufficient
to cover P. aeruginosa and other less susceptible bacteria in patients suffering from severe sepsis and septic
shock.

• Recommended doses of meropenem resulted in adequate concentrations to cover P. aeruginosa and other less susceptible bacteria in 75% of patients.

• In patients treated with piperacillin-tazobactam, renal dysfunction is associated
with a better adequacy of drug concentrations compared with normal renal function.

• Therapeutic drug monitoring is necessary to optimize β-lactam concentrations as
no clinical or biological variable can predict β-lactam concentrations in this population.

Competing interests

FST, FJ, JLV, TD and PFL have received honoraria for lectures from Astra Zeneca. JLV
is also on the speakers list of GlaxoSmithKline. The other authors declare that they
have no competing interests.

Authors' contributions

FJ and PFL conceived the study protocol. FST, FJ, PFL, TD, XW, BL and HS participated
in the design and coordination of the study. ID and PW performed the PK analyses.
FST, PFL, DDB, JLV and FJ drafted the present manuscript. All authors read and approved
the final manuscript.

Acknowledgements

We thank all the nurses and doctors who contributed to this study. The study was supported
by grants from AstraZeneca, Wyeth Pharmaceuticals, GlaxoSmithKline Pharmaceuticals,
and Bristol-Myers Squibb. These companies had no involvement in the writing of the
paper or in the decision to submit for publication.

McKinnon PS, Paladino JA, Schentag JJ: Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory
concentration (T > MIC) as predictors of outcome for cefepime and ceftazidime in serious
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Jaruratanasirikul S, Sriwiriyajan S, Punyo J: Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated
pneumonia following administration by 3-hour infusion or bolus injection.